DD297332A5 - NEW ORAL DRUG PREPARATION TO IMPROVE AVAILABILITY - Google Patents

Abstract

The invention relates to a novel pharmaceutical preparation for improving the bioavailability of a medicament. The incorporation of natural proteins into the composition results in a controllable release of the active ingredient. This makes forms with unit doses possible, which are especially applicable to the dihydropyridines which have calcium antagonistic properties. These special forms can be used to carry out daily therapeutic revenues.

Description

For this 7 pages drawings

The invention relates to a new pharmaceutical preparation which makes it possible to improve the bioavailability of medicaments and

especially those who form the class of calcium inhibitors.

These include dihydropyridine derivatives which have excellent cardiovascular properties, their use

However, is limited by problems of in vivo solution, ie in an aqueous environment.

For this reason, the Applicant has endeavored to provide a special drug preparation to be used in a daily Ingesting the in vivo release of such agents regardless of the solubility of these agents to achieve

be able to adjust sufficient plasma levels.

The essence of the invention is the choice of a specific protein substrate with which this goal can be achieved. It is known that an active ingredient is a water-soluble crystalline substrate, such as polyethylene glycol or Polyvinylpyrrolidone is added in the form of a dispersing agent to obtain depot forms, as for example in

French Patent 2,565,822. The resulting dispersion, which is compatible with conventional excipients in

However, as described in the above-mentioned patent, "a

rapid delivery of the drug when it enters the stomach, "provided it has been protected for gastrointestinal absorption by a fatty acid glycine ester or by an enteric coating

Side effects, such as headache, redness, etc., result. The experiment has shown that the preparation of these dispersions under the known physicochemical Conditions generally leads to a product of solid blocks that are heavy. The grinding has a warming to As a result, the drug becomes unstable and there is at least a risk of partial decomposition. In the other cases will be

sticky, difficult-to-recover and thus industrially difficult-to-use substances ("Stability Problems under specialconsideration of solid dispersion of drugs", S.T.P.Pharma 1 | 7] 660-665 (1985)).

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With the numerous solutions proposed in the literature, it has not been possible to date to meet the absorption conditions which provide an immediate effect of the drug after ingestion and regularly lasting over 24 hours.

The object of this invention is to propose an oral form of such medicaments by which a constant effect is obtained over a period of 24 hours with a single daily intake, even if these constituents are soluble in water or not at all. The control of bioavailability requires, depending on the case, the slowdown ο Jc; the acceleration, but above all, the regularity of the diffusion.

The following example illustrates the practical meaning. Oxodipiri (or 1,4-dihydro-4- (2 '-, 3'-methylenedioxyphenyl) -methyl- and ethyl-3,5-pyridinedicarboxlate) described in French Patent No. 2,562,069 has shown a strong calchemizing effect. which can be used in the treatment of cardiovascular disorders, such as hypertension. Its low solubility in water, however, appears to limit its uses in pharmaceutical compositions.

The use of conventional solvents such as non-aqueous solvents (for example, ethanol) or the addition of wetting agents is now not always compatible with in vivo administration.

The investigation of the in vitro dissolution kinetics, which was carried out on the one hand in distilled water and on the other hand in intestinal juice, shows that an improvement is already achieved when an oxodipine-polyvinylpyrrolidone coprecipitate is used instead of pure oxodipin, the solution of which is slow and runs, which expressed in a slow and limited in vivo absorption.

However, this solid dispersion has the deficiencies already highlighted in known processes, that is, it releases very fast and intensively almost all of the drug, thereby failing to provide good control of bioavailability over one day.

Figure 1 shows in vivo human intestinal in vivo dissolution kinetics of two oxodipine preparations administered orally:

Pure oxodipine "powder" and "oxodipine solid solution" in polyvinylpyrrolidone versus an oral hydroalcoholic reference solution which provides 100% absorption, each containing a dose of 20mg of active ingredient. It can be seen that the "powder" releases at most 20% of the administered 20 mg, while the "solid solution" releases 100%, which are almost completely absorbed almost immediately.

Applicant has discovered in the course of his research that by combining a solid solution (of oxodipin with polyvinylpyrrolidone, for example) with proteins a satisfactory therapeutic system could be achieved which would ensure control of absorption and bioavailability. Two of these proteins have emerged particularly well, since within this combination it is possible to achieve the following goals:

- Dissolving the insoluble constituents

- Control of the release of soluble constituents

- Availability for the organism of a fast (application) dose and a controlled dose

- Improvement of in vivo dissolution, absorption and bioavailability in humans.

These natural proteins are taken from skimmed fresh milk and are commercially available under the names PROSOBEL-L85 and PROSOBEL-L60.

Tablets and gelatin capsules with oxodipine or other dihydropyridines as active ingredient were prepared. Then they were given to healthy volunteers orally; the drug plasma levels were controlled at regular intervals.

example 1

Preparation of an Oxodipine Polyvinylpyrrolidone Coprugate

5800 ml of pure ethanol are added to a 20 l reaction vessel, after which 2600 g of polyvinylpyrrolidone are added in portions with stirring. It is heated to about 3O ⁰ C to dissolve everything, then 650g Oxodipin be added. The whole is heated slowly to i-ngefähr 8O ⁰ C to achieve complete solution and allowed to stand.

Some crystals have been on the walls :. Jes balloons regressed. It is added 1 liter of ethanol and the whole again heated to 8O ⁰ C to dissolve the product. It is 24 hours at ambient temperature (about 2O ⁰ C) allowed to stand, and then the solution is evaporated. The resulting product is dried for several hours at 80 ⁰ C, ground and then sieved with a sieve of 400 pm.

Dosing by UV spectrometry gave the following results (360 nm) OXOPIDIN: 19.9% PVP: 77.6% Ethanol residue: 1200 ppm

Example 2

Preparation of gelatin capsules with 20mg oxodipine

In the container of a mixer "Turbula" the ingredients (A) are introduced and homogenized for 10 minutes.

It is mixed with the lubricant ingredients (B), and gelatin capsules No. 1 are filled with this mixture.

Reference capsules F Co-precipitated oxodipine 0.050 g (A) (with 20%, i.e. 10 mg oxodipine) HPMC15 000 0.018 g (Hydroxypropylmethyl cellulose) PROSOBEL-L 60 0.113 g STARCH 0.014 g LACTOSE 0.032 g 0,227 g TALK (2301-ZA) 0.0022 g (B) Mg stearate 0.0022 g

For a gelatin capsule with a content of 0.2314g

Reference capsule G

The same quantities and components are used, but PROSOBEL L60 is replaced by PROSOBEL-L85.

Example 3 A single-layered tablet is made by physically combining (gluing) two "partial tablets" (C)

is formed for rapid release and (D) for slow release and which contains the active ingredient, the conventional

Drugs and PROSOBEI-L85 or L60 (which provide similar results) are added. The whole forms a therapeutic system that provides the controlled release of the application dose and the maintenance dose

allows.

The preferred antoelics of these partial tablets are:

Partial tablet C (in% by weight) 23.4 Oxodipincopräzipitat 70.1 ELCEMA-G 250 6.5 PRIMOJEL (carboxymethyl starch) 100 Partial tablet D (in% by weight) 22 Oxodipincopräzipitat 50 PROSOBEL (L 85 or L 60) 8th HPMC 6 Strength 4 lactose 8th COMPRITOL 1 talc 1 Mg stearate

100

As an example, the partial tablet C is dosed with 5 mg oxodipine and the partial tablet D with 10,15,20 mg oxodipine, whereby Unit dosages of 15.20 and 25mg of oxodipine become available. The novel pharmaceutical forms of the invention have been the subject of in vitro and in vivo studies. FIG. 1 expresses the percentage of active ingredient absorbed in the human organism (intestinal juice) at the same dose

pure oxodipine (powder) and in solid solution of oxodipine-Polyvinylpyrrolidonsopräzipitat (with 20% oxodipine). It can be seen that in the case of the solid solution an immediate and massive oxodipine release occurs (which elicited the side reactions already described), whereas in the case of pure oxodipine no more than 20% absorption was achieved, which is insufficient.

Capsules F and G (according to Example 2) were administered to 6 healthy volunteers and the oxodipine plasma levels

and the percentage of oxodipine absorbed were monitored over the entire 24 hour period. The

Results were compared with those obtained with the known forms (hydroalcoholic solution, coprecipitate, pure Oxodipine powder). FIG. 2 shows the results set up after 3 hours and illustrates maximum concentrations compared to the Coprecipitate are reduced by half. FIG. 3 shows that the portions absorbed from the PROSOBEL-containing gelatin capsules range from a too fast one

(Coprecipitate) or too slow absorption (powder), which is proof of better absorption control with

PROSOBEL is. On the other hand, it can be seen that the selected PROSOBEL species (L60 or L85) does not have the in vivo result in humans

affected.

Six healthy volunteers were given tablets of Example 3 at doses of 15.20 and 25 mg oxodipine. Figure 4 and Table I represent the evolution of plasma concentrations over the entire 24 hour period

was controlled. The results are compared with those obtained by oral administration after administration of the powder and coprecipitate.

The example of the 20 mg tablet is developed and compared with the same dose in the known forms (Table II). This comparison emphasizes that the achieved and controlled levels are in between those of the known ones Forms emerge (Figure 5), and that they are distributed over the same period of 24 hours. It is special

determine that the coprecipitate leads to a blood concentration of 95 ng / ml serum in less than one hour and that

Figure 5 shows the corresponding curve only from 1.50 h (43 ng / ml) for reasons of clarity of the drawing. The analysis of the results (Figure 6) confirms the good control of the dissolution absorption of the active ingredient from the Tablet form. The results given in Table III show that the bioavailability of each form after 12 hours elapsed Coprecipitate completely (100%), the powder of pure oxodipine low (31%) and excellent in tablets (86 to 92%). These results were confirmed by those that the applicant with other dihydropyridines and especially the NIFEDIPINE has achieved. Figure 7 shows the parallel behavior between oxodipine and nifedipine. The solution kinetics in these two Dihydropyridines are very rapidly (nifedipine in the raw state highly water soluble), were added by addition of PROSOBEL in the

the same quantities as in Examples 2 and 3 dominated.

From this it can be concluded that PROSOBEL provides the solution in an aqueous environment to the skilled worker in quite unexpected ways

slows down and the achievement of original and new pharmaceutical forms of dihydropyridines with controlled

Bioavailability makes possible.

Of course, the examples set forth are not intended to limit the invention, which is fully applicable and effective when the PROSOBEL-containing mixture is in the form of granules, capsules or in any other solid or semi-solid form, such as mucous membrane gel or paste or as well Suspension, is present. Depending on the form considered or depending on the water solubility of the active ingredient used, the experiment has shown that the addition of 10 to 70% PROSOBEL the bioavailability d6s drug can be adapted to the desired plasma levels.

Table I

Tablet 16 mg Tablet 20 mg Tablet 25 mg concentration concentration concentration Time (h) in ng / ml in ng / ml in ng / ml 0.00 0.0 0.0 0.0 0.17 2.0 1.8 2.9 0.33 10.0 11.9 12.0 0.50 19.5 17.2 16.1 0.66 19.9 18.1 17.0 0.83 17.8 17.1 18.6 1.00 17.0 16.2 15.7 1.25 18.2 14.2 14.4 1.50 16.4 12.8 14.3 2.00 16.0 12.3 12.0 3.00 12.2 13.8 14.4 4.00 8.0 12.5 14.7 6.00 3.7 8.4 9.3 8.00 2.0 4.2 5.G 10.00 1.7 3.4 4.3 12,00 1.6 2.8 3.2 14.00 0.9 2.1 2.8 24.00 - 1.0 1.3 28,00 - 0.6 0.6

Plasma concentration observed after single administration of the 15,20,25mg tablets in healthy individuals (mean). Table II

Powder 20 mg Copräzipitat20mg Tablet 20 mg concentration concentration concentration Time (h) in ng / ml in ng / ml in ng / ml 0.00 0.0 0.0 0.0 0.17 1.2 1.4 1.8 0.33 1.4 28.9 11.9 0.50 2.7 76.3 17.2 0.66 4.2 95.5 18.1 0.83 5.0 93.4 17.1 1.00 6.0 75.8 16.2 1.25 6.8 55.7 14.2 1.50 6.5 43.4 12.8 2.00 6.2 28.2 13.3 3.00 5.1 15.7 13.8 4.00 4.0 10.5 12.5 6.00 2.4 5.0 8.4 8.00 1.6 3.0 4.2 10.00 1.4 2.2 3.4 12,00 1.2 1.9 2.8 14.00 1.0 1.4 2.1 24.00 1.2 1.0 1.0 28,00 - - 0.6

Plasma levels observed after single oral administration of droi oxodipine forms in 6 healthy subjects (mean).

Table III

Dose percentages which have passed into the organism after absorption and passage through the liver

Time (h) Pl'lvnr coprecipitate tablet tablet tablet 20 mg 15mg 20 mg 25mg 0.00 - - - - - 0.17 2.5 32 2.4 2.1 5.9 0.33 1.6 60 12.6 12.1 15 0.50 · 4.5 75 26.2 20.3 23.5 0.66 6.6 87 32.7 24.5 26 0.83 7.0 93 35.5 26 28.1 1.00 9.3 96 38.9 31.9 28.3 1.25 11 96 46.4 31.0 30.5 1.50 11.4 97 50.2 33 32.8 2.00 14.0 97 59.0 41.1 39.2 3.00 16.6 100 68.7 51.0 48.1 4.00 18 100 72.7 61.7 53.7 6.00 19.8 100 74.5 71.1 61.0 8.00 21.2 100 75.6 74.8 63.8 10.00 22.6 100 77.2 78.5 66.6 12,00 23.8 100 79.2 81.1 68.2 relative bioavailability - - - - - availability in comparison to the solution 31% 100 86% 92% 88%

Fig. 1: Kinetics of intestinal in vivo solution of two oxodipine preparations in humans. (Mean results for 6 people)

1% dissolved 2 solid solution (20%) 3 powder

Fig. 2: 1 Mean subject 2 Coprecipitate 3 Solution 4 Form F 5 Form G 6 Time Fig. 3: Mean kinetics

1% in vivo absorbs 2 powders 3 solid solution 4 dissolved (%) 5 undissolved (%) In vivo solution kinetics depending on the solid solution () of forms F (♦) and G (O) according to Example 2 and of Powder «>) ·

The representation of the dissolved and unresolved total shares is for each of the shapes in the upper right corner. Fig. 4: 1 mean η = 6 subjects 2 tablet 25 mg 3 tablet 20 mg 4 tablet 15 mg Fig. 5-6: 1 means = 6 subjects 2 coprecipitate 3 tablet 20mg 4 powder 20mg Fig. 7: In vitro solution kinetics as a function of time for the same oxodipine and nifedipine preparations with PROSOBEL (below or without PROSOBEL (top)

1% solved 2 time

Claims (16)

A method of controlling the bioavailability of an oral medicament consisting of adding to the ineffective excipients 10 to 70% by weight of natural proteins. 2. The method of claim 1, wherein the natural proteins are derived from milk. 3. The method according to any one of claims 1 or 2, wherein the natural proteins are PROSOBEL. A controlled bioavailability pharmaceutical composition containing at least one active agent acting as a calcium inhibitor, common excipients and natural proteins. The pharmaceutical composition according to claim 4, wherein the calcium inhibiting substance is a dihydropyridine. 6. A pharmaceutical composition according to any one of claims 4 or 5, wherein the active ingredient is oxodipine. 7. A pharmaceutical composition according to any one of claims 4 or 5, wherein the active ingredient is nifedipine. 8. A pharmaceutical composition according to any one of claims 4 to 7, wherein the natural proteins are derived from milk. A pharmaceutical composition according to any one of claims 4 to 8, wherein the proteins are PROSOBEL. 10. Pharmaceutical composition according to one of claims 4, 5, 6, 8 or 9, characterized in that it contains nifedipine and PROSOBEL L60. 11. A pharmaceutical composition according to any one of claims 4,5,6,8 or 9, characterized in that it contains oxodipine and PROSOBEL L85. 12. A pharmaceutical composition according to any one of claims 4,5,7,8 or 9, characterized in that it contains nifedipine and PROSOBEL L60. 13. Pharmaceutical composition according to one of claims 4, 5, 7, 8 or 9, characterized in that it contains nifedipine and PROSOBEL L85. 14. A pharmaceutical composition according to any one of claims 4 to 13, characterized in that it is contained in a gelatin capsule which represents a unit daily dose. 15. A pharmaceutical composition according to any one of claims 4 to 13, characterized in that it is in the form of tablets representing a unit daily dose. 16. A pharmaceutical composition according to claim 15, characterized in that the tablet consists of two layers, wherein one of the layers containing the application dose for rapid release and the other slow-release.